Fentanyl enhances the excitability of rapidly adapting receptors to cause cough via the enhancement of histamine release in the airways

BACKGROUND: Although the mechanism of fentanyl-induced cough is unclear, several lines of evidence suggest that allergic mediators, such as histamine, may play a role in the production of fentanyl-induced coughs. The aim of this study was to explore the effects of fentanyl on cough sensitivity to inhaled citric acid and on histamine release in BALF in mice. METHODS: The cough reflex was induced by the inhalation of citric acid. Male ICR mice were exposed to a nebulized solution of citric acid at a concentration of 0.1 M under conscious and identical conditions using a body plethysmograph. The number of coughs produced per 3-min period of exposure to citric acid was counted. Histamine content in BALF was analyzed by HPLC post-column derivatization and fluorescence detection. RESULTS: Intravenous administration of fentanyl increased the number of citric acid-induced coughs. The fentanyl-induced enhancement of the number of citric acid-induced coughs was abolished in mice that had been pretreated with moguisteine, a rapidly adapting receptor (RAR) antagonist or fexofenadine, a histamine H1 receptor antagonist. Fentanyl significantly increased the concentration of histamine in BALF. CONCLUSION: The results of this study suggest that fentanyl enhances the excitability of RARs to cause cough, and enhancement of histamine release in the airways may some how be related to this change.